Oxygenated-Heterocycle containing sulfonamide inhibitors of aspartyl protease

ABSTRACT

The present invention relates to a novel class of sulfonamides which are aspartyl protease inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a novel class of sulfonamides which areaspartyl protease inhibitors. In one embodiment, this invention relatesto a novel class of HIV aspartyl protease inhibitors characterized byspecific structural and physicochemical features. This invention alsorelates to pharmaceutical compositions comprising these compounds. Thecompounds and pharmaceutical compositions of this invention areparticularly well suited for inhibiting HIV-1 and HIV-2 proteaseactivity and consequently, may be advantageously used as anti-viralagents against the HIV-1 and HIV-2 viruses. This invention also relatesto methods for inhibiting the activity of HIV aspartyl protease usingthe compounds of this invention.

BACKGROUND OF THE INVENTION

The human immunodeficiency virus ("HIV") is the causative agent foracquired immunodeficiency syndrome ("AIDS")--a disease characterized bythe destruction of the immune system, particularly of CD4⁺ T-cells, withattendant susceptibility to opportunistic infections--and its precursorAIDS-related complex ("ARC")--a syndrome characterized by symptoms suchas persistent generalized lymphadenopathy, fever and weight loss.

As in the case of several other retroviruses, HIV encodes the productionof a protease which carries out post-translational cleavage of precursorpolypeptides in a process necessary for the formation of infectiousvirions (S. Crawford et al., "A Deletion Mutation in the 5' Part of thepol Gene of Moloney Murine Leukemia Virus Blocks Proteolytic Processingof the gag and pol Polyproteins", J. Virol., 53, p. 899 (1985)). Thesegene products include pol, which encodes the virion RNA-dependent DNApolymerase (reverse transcriptase), an endonuclease, HIV protease, andgag, which encodes the core-proteins of the virion (H. Toh et al.,"Close Structural Resemblance Between Putative Polymerase of aDrosophila Transposable Genetic Element 17.6 and pol gene product ofMoloney Murine Leukemia Virus", EMBO J., 4, p. 1267 (1985); L. H. Pearlet al., "A Structural Model for the Retroviral Proteases", Nature., pp.329-351 (1987); M. D. Power et al., "Nucleotide Sequence of SRV-1, aType D Simian Acquired Immune Deficiency Syndrome Retrovirus", Science,231, p. 1567 (1986)).

A number of synthetic anti-viral agents have been designed to targetvarious stages in the replication cycle of HIV. These agents includecompounds which block viral binding to CD4⁺ T-lymphocytes (for example,soluble CD4), and compounds which interfere with viral replication byinhibiting viral reverse transcriptase (for example, didanosine andzidovudine (AZT)) and inhibit integration of viral DNA into cellular DNA(M. S. Hirsh and R. T. D'Aqulia, "Therapy for Human ImmunodeficiencyVirus Infection", N.Eng.J.Med., 328, p. 1686 (1993)). However, suchagents, which are directed primarily to early stages of viralreplication, do not prevent the production of infectious virions inchronically infected cells. Furthermore, administration of some of theseagents in effective amounts has led to cell-toxicity and unwanted sideeffects, such as anemia and bone marrow suppression.

More recently, drug design efforts have been directed toward creatingcompounds which inhibit the formation of infectious virions byinterfering with the processing of viral polyprotein precursors.Processing of these precursor proteins requires the action ofvirus-encoded proteases which are essential for replication (Kohl, N. E.et al. "Active HIV Protease is Required for Viral Infectivity" Proc.Natl. Acad. Sci. USA, 85, p. 4686 (1988)). The anti-viral potential ofHIV protease inhibition has been demonstrated using peptidal inhibitors.Such peptidal compounds, however, are typically large and complexmolecules that tend to exhibit poor bioavailability and are notgenerally consistent with oral administration. Accordingly, the needstill exists for compounds that can effectively inhibit the action ofviral proteases, for use as agents for preventing and treating chronicand acute viral infections. Such agents would be expected to act aseffective therapeutic agents in their own right. In addition, since theyact at a separate stage in the virus life cycle from previouslydescribed antiretroviral agents, the administration of a combination ofagents would be expected to result in increased therapeutic efficacy.

SUMMARY OF THE INVENTION

The present invention provides a novel class of compounds, andpharmaceutically acceptable derivatives thereof, that are useful asinhibitors of aspartyl proteases, in particular, HIV aspartyl protease.These compounds can be used alone or in combination with othertherapeutic or prophylactic agents, such as anti-virals, antibiotics,immunomodulators or vaccines, for the treatment or prophylaxis of viralinfection.

According to a preferred embodiment, the compounds of this invention arecapable of inhibiting HIV viral replication in human CD₄ ⁺ cellsincluding T-cells, monocytic lines including macrophages and dendrocytesand other permissive cells. These compounds are useful as therapeuticand prophylactic agents to treat or prevent infection by HIV-1 andrelated viruses which may result in asymptomatic infection, AIDS-relatedcomplex ("ARC"), acquired immunodeficiency syndrome ("AIDS"), or similardisease of the immune system.

It is a principal object of this invention to provide a novel class ofsulfonamides which are aspartyl protease inhibitors, and particularly,HIV aspartyl protease inhibitors. This novel class of sulfonamides isrepresented by formula I: ##STR1## wherein: each R¹ is independentlyselected from the group consisting of --C(O)--, --S(O)₂ --,--C(O)--C(O)--, --O--C(O)--, --O--S(O)₂, --NR² --S(O)₂ --, --NR²--C(O)-- and --NR² --C(O)--C(O)--;

each A is independently selected from the group consisting of 5-7membered non-aromatic monocyclic oxygenated heterocycles containing from1-3 endocyclic oxygens, which may be optionally benzofused, optionallyattached through a C₁ -C₃ alkyl linker and optionally fused with a 5-7membered monocyclic heterocycle containing from 1-2 endocyclicheteroatoms, and wherein tetrahydrofuran andtetrahydrofurotetrahydrofuran are expressly excluded;

each Ht is independently selected from the group consisting of C₃ -C₇carbocycle; C₆ -C₁₀ aryl; phenyl fused with heterocycle; andheterocycle; wherein any member of said Ht may be optionally substitutedwith one or more substituents selected from the group consisting of oxo,--OR², --R², --N(R²)(R²), --NHOH, --R² --OH, --CN, --CO₂ R²,--C(O)--N(R²)(R²), --S(O)₂ --N(R²)(R²), --N(R²)--C(O)--R², --C(O)--R²,--S(O)_(n) --R², --OCF₃, --S(O)_(n) --R⁶, --N(R²)--S(O)₂ (R²), halo,--CF₃, --NO₂, --R⁶ and --O--R⁶ ;

each R² is independently selected from the group consisting of H and C₁-C₃ alkyl optionally substituted with R⁶ ;

each R³ is independently selected from the group consisting of H, Ht, C₁-C₆ alkyl and C₂ -C₆ alkenyl wherein any member of said R³, except H,may be optionally substituted with one or more substituents selectedfrom the group consisting of --OR², --C(O)--NH--R², --S(O)_(n)--N(R²)(R²), Ht, --CN, --SR², --CO₂ R², NR² --C(O)--R² ;

each n is independently 1 or 2;

each D and D' is independently selected from the group consisting of R⁶; C₁ -C₅ alkyl, which may be optionally substituted with one or moregroups selected from --OR², --R³, --S--R⁶ --O--R⁶ and R⁶ ; C₂ -C₄alkenyl, which may be optionally substituted with one or more groupsselected from the group consisting of --OR², --R³, --O--R⁶ and R⁶ ; andC₁ -C₆ carbocycle, which may be optionally substituted with or fusedwith R⁶ ;

each E is independently selected from the group consisting of Ht;--O--Ht; Ht--Ht; --O--R³ ; --NR² R³ ; C₁ -C₆ alkyl, which may beoptionally substituted with one or more groups selected from the groupconsisting of R⁴ and Ht; C₂ -C₆ alkenyl, which may be optionallysubstituted with one or more groups selected from the group consistingof R⁴ and Ht; and phenyl fused with 5-6 membered heterocycle;

each R⁴ is independently selected from the group consisting of --OR²,--C(O)--NHR², --S(O)₂ --NHR², halo, --NR² --C(O)--R² and --CN;

each R⁵ is independently selected from the group consisting of H and C₁-C₄ alkyl optionally substituted with aryl; and

each R⁶ is independently selected from the group consisting of aryl,carbocycle and heterocycle, wherein said aryl, carbocycle or heterocyclemay be optionally substituted with one or more groups selected from thegroup consisting of oxo, --OR⁵, --R⁵, --N(R⁵)(R⁵), --N(R⁵)--C(O)--R⁵,--OH, --CN, --CO₂ R⁵, --C(O)--N(R⁵)(R⁵), halo and --CF₃.

It is also an object of this invention to provide pharmaceuticalcompositions comprising the sulfonamides of formula I and methods fortheir use as inhibitors of HIV aspartyl protease.

DETAILED DESCRIPTION OF THE INVENTION

In order that the invention herein described may be more fullyunderstood, the following detailed description is set forth. In thedescription, the following abbreviations are used:

    ______________________________________                                        Designation   Reaqent or Fragment                                             ______________________________________                                        Ac            acetyl                                                          Me            methyl                                                          Et            ethyl                                                           Bn            benzyl                                                          Trityl        triphenylmethyl                                                 Asn           D- or L-asparagine                                              Ile           D- or L-isoleucine                                              Phe           D- or L-phenylalanine                                           Val           D- or L-valine                                                  Boc           tert-butoxycarbonyl                                             Cbz           benzyloxycarbonyl (carbobenzyloxy)                              DCC           dicyclohexylcarbodiimide                                        DBU           1,8-diazabicycl6(5.4.0)undec-7-ene                              DIC           diisopropylcarbodiimide                                         DIEA          diisopropylethylamine                                           DMF           dimethylformamide                                               DMSO          dimethylsulfoxide                                               EDC           1-(3-dimethylaminopropyl)-3-                                                  ethylcarbodiimide hydrochloride                                 EtOAc         ethyl acetate                                                   Fmoc          9-fluorenylmethoxycarbonyl                                      HOBt          1-hydroxybenzotriazole                                          HQSU          1-hydroxysuccinimide                                            iBu           iso-butyl                                                       NCA           N-carboxyanhydride                                              t-Bu          tert-butyl                                                      TFA           trifluoroacetic acid                                            THP           tertrahydropyran                                                THF           tetrahydrofuran                                                 TMSCl         chlorotrimethylsilane                                           ______________________________________                                    

The following terms are employed herein:

Unless expressly stated to the contrary, the terms "--SO₂ --" and"--S(O)₂ --" as used herein refer to a sulfone or sulfone derivative(i.e., both appended groups linked to the S), and not a sulfinate ester.

The term "backbone" refers to the structural representation of acompound of this invention, as set forth in the figures drawn in thisapplication.

For the compounds of formula I, and intermediates thereof, thestereochemistry of the explicitly shown hydroxyl is defined relative toD on the adjacent carbon atom, when the molecule is drawn in an extendedzig-zag representation (such as that drawn for compounds of formula VI).If both OH and D reside on the same side of the plane defined by theextended backbone of the compound, the stereochemistry of the hydroxylwill be referred to as "syn". If OH and D reside on opposite sides ofthat plane, the stereochemistry of the hydroxyl will be referred to as"anti".

As used herein, the term "alkyl", alone or in combination with any otherterm, refers to a straight-chain or branch-chain saturated aliphatichydrocarbon radical containing the specified number of carbon atoms, orwhere no number is specified, preferably from 1-10 and more preferablyfrom 1-5 carbon atoms. Examples of alkyl radicals include, but are notlimited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isoamyl, n-hexyl and the like.

The term "alkenyl", alone or in combination with any other term, refersto a straight-chain or branched-chain mono- or poly-unsaturatedaliphatic hydrocarbon radical containing the specified number of carbonatoms, or where no number is specified, preferably from 2-10 carbonatoms and more preferably, from 2-6 carbon atoms. Examples of alkenylradicals include, but are not limited to, ethenyl, E- and Z-propenyl,isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl,E- and Z-hexenyl, E,E-, E,Z-, Z,E- and Z,Z-hexadienyl and the like.

The term "aryl", alone or in combination with any other term, refers toa carbocyclic aromatic radical (such as phenyl or naphthyl) containingthe specified number of carbon atoms, preferably from 6-14 carbon atoms,and more preferably from 6-10 carbon atoms. Examples of aryl radicalsinclude, but are not limited to phenyl, naphthyl, indenyl, indanyl,azulenyl, fluorenyl, anthracenyl and the like.

The term "cycloalkyl", alone or in combination with any other term,refers to a cyclic saturated hydrocarbon radical containing thespecified number of carbon atoms, preferably from 3-7 carbon atoms.Examples of cycloalkyl radicals include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and thelike.

The term "cycloalkenyl", alone or in combination with any other term,refers to a cyclic hydrocarbon radical containing the specified numberof carbon atoms with at least one endocyclic carbon-carbon bond. Whereno number of carbon atoms is specified, a cycloalkenyl radicalpreferably has from 5-7 carbon atoms. Examples of cycloalkenyl radicalsinclude, but are not limited to, cyclopentenyl, cyclohexenyl,cyclopentadienyl and the like.

The term "THF" refers to a tetrahydrofuran ring attached at any ringcarbon resulting in a stable structure.

The term "carbocycle" refers to a stable non-aromatic 3- to 8-memberedcarbon ring radical which may be saturated, mono-unsaturated orpoly-unsaturated. The carbocycle may be attached at any endocycliccarbon atom which results in a stable structure. Preferred carbocycleshave 5-6 carbons. Examples of carbocycle radicals include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl and the like.

The term "heterocycle", unless otherwise defined herein, refers to astable 3-7 membered monocyclic heterocyclic ring or 8-11 memberedbicyclic heterocyclic ring which is either saturated or unsaturated, andwhich may be optionally benzofused if monocyclic. Each heterocycleconsists of one or more carbon atoms and from one to four heteroatomsselected from the group consisting of nitrogen, oxygen and sulfur. Asused herein, the terms "nitrogen and sulfur heteroatoms" include anyoxidized form of nitrogen and sulfur, and the quaternized form of anybasic nitrogen. In addition, any ring nitrogen may be optionallysubstituted with a substituent R², as defined herein for compounds offormula I. A heterocycle may be attached at any endocyclic carbon orheteroatom which results in the creation of a stable structure. Aheterocycle may be attached at any endocyclic carbon or heteroatom whichresults in the creation of a stable structure. Preferred heterocyclesinclude 5-7 membered monocyclic heterocycles and 8-10 membered bicyclicheterocycles. Preferred heterocycles defined above include, for example,benzimidazolyl, imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl,isoquinolyl, indolyl, indazolyl, indazolinolyl, perhydropyridazyl,pyridazyl, pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl,pyrazinyl, quinoxolyl, piperidinyl, pyranyl, pyrazolinyl, piperazinyl,pyrimidinyl, pyridazinyl, morpholinyl, thiamorpholinyl, furyl, thienyl,triazolyl, thiazolyl, β-carbolinyl, tetrazolyl, thiazolidinyl,benzofuranoyl, thiamorpholinyl sulfone, oxazolyl, benzoxazolyl,oxopiperidinyl, oxopyrroldinyl, oxoazepinyl, azepinyl, isoxazolyl,isothiazolyl, furazanyl, tetrahydropyranyl, tetrahydrofuranyl,thiazolyl, thiadiazoyl, dioxolyl, dioxinyl, oxathiolyl, benzodioxolyl,dithiolyl, thiophenyl, tetrahydrothiophenyl, dioxanyl, dioxolanyl,tetrahydrofurotetrahydrofuranyl, tetrahydropyranotetrahydrofuranyl,tetrahydrofurodihydrofuranyl, tetrahydropyranodihydrofuranyl,dihydropyranyl, dihydrofuranyl, dihydrofurotetrahydrofuranyl,dihydropyranotetrahydrofuranyl, sulfolanyl and the like.

The term "halo" refers to a radical of fluorine, chlorine, bromine oriodine.

The term "linker" refers to a structural unit through which two othermoieties are joined. For example, the term "C₁ -C₃ alkyl linker" refersto a 1-3 carbon unit which attaches two other moieties together.

The term "oxygenated heterocycle", unless expressly modified to thecontrary, refers to an aromatic or non-aromatic, preferablynon-aromatic, 5-7 membered monocyclic or 8-11 membered bicyclicheterocycle containing 1-3, and more preferably 1-2, endocyclic oxygenheteroatoms and 0-2 endocyclic nitrogen or sulfur heteroatoms.Preferably, such oxygenated heterocycles contain only endocyclic oxygenheteroatoms. Examples of oxygenated heterocycles, include, but are notlimited to: dioxanyl, dioxolanyl, tetrahydrofuranyl,tetrahydrofurotetrahydrofuranyl, tetrahydropyranyl,tetrahydropyranotetrahydrofuranyl, tetrahydrofurodihydrofuranyl,tetrahydropyranodihydrofuranyl, dihydropyranyl, dihydrofuranyl,dihydrofurotetrahydrofuranyl and dihydropyranotetrahydrofuranyl and thelike.

The terms "HIV protease" and "HIV aspartyl protease" are usedinterchangeably and refer to the aspartyl protease encoded by the humanimmunodeficiency virus type 1 or 2. In a preferred embodiment of thisinvention, these terms refer to the human immunodeficiency virus type 1aspartyl protease.

The term "anti-viral agent" or "anti-retroviral agent" refers to acompound or drug which possesses viral inhibitory activity. Such agentsinclude reverse transcriptase inhibitors (including nucleoside andnon-nucleoside analogs) and protease inhibitors. Preferably the proteaseinhibitor is an HIV protease inhibitor. Examples of nucleoside analogreverse transcriptase inhibitors include, but are not limited to,zidovudine (AZT), dideoxycytidine (ddC), didanosine (ddI), stavudine(d4T), 3TC, 935U83, 1592U89 and 524W91. Examples of non-nucleosideanalog reverse transcriptase inhibitors include, but are not limited todelavirdine (U90) and nevirapine. Examples of HIV protease inhibitorsinclude, but are not limited to, saquinavir (Ro 31-8959), MK 639, ABT538 (A80538), AG 1343, XM 412, XM 450, BMS 186318 and CPG 53,437.

The term "leaving group" or "LG" refers to groups readily displaceableby a nucleophile, such as an amine, alcohol, phosphorous or thiolnucleophile or their respective anions. Such leaving groups are wellknown and include carboxylates, N-hydroxysuccinimide,N-hydroxybenzotriazole, halogen (halides), triflates, tosylates,mesylates, alkoxy, thioalkoxy, phosphinates, phosphonates and the like.Other potential nucleophiles include organometallic reagents known tothose skilled in the art. In addition, the term "leaving group" or "LG"is meant to encompass leaving group precursors (i.e., moieties that canbe easily converted to a leaving group upon simple synthetic proceduressuch as alkylation, oxidation or protonation). Such leaving groupprecursors and methods for converting them to leaving groups are wellknown to those of ordinary skill in the art. Leaving group precursorsinclude, for instance, secondary and tertiary amines. By way of example,the moiety --N(R₃)(R₄), while not itself a leaving group, is encompassedby the term "leaving group" or "LG" because it can be readily convertedto a leaving group such as --N⁺ CH₃ (R₃)(R₄).

The term "protecting group" refers to a suitable chemical group whichmay be attached to a functional group and removed at a later stage toreveal the intact functional group. Examples of suitable protectinggroups for various functional groups are described in T. W. Greene andP. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., JohnWiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser'sReagents for Organic Synthesis, John Wiley and Sons (1994); L. Paquette,ed. Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995).

The term "silyl" refers to a trisubstituted silicon radical in which thesubstituents are independently C₁ -C₈ alkyl, C₅ -C₇ aryl or C₅ -C₇carbocycle. Examples of silyl groups include, but are not limited to,trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl,t-butyldiisopropylsilyl, t-butyldiphenylsilyl, triphenylsilyl,cyclohexyldimethylsilyl and the like.

The term "pharmaceutically effective amount" refers to an amounteffective in treating HIV infection in a patient either as monotherapyor in combination with other agents. The term "treating" as used hereinrefers to the alleviation of symptoms of a particular disorder in apatient or the improvement of an ascertainable measurement associatedwith a particular disorder. Specifically, with respect to HIV, effectivetreatment using the compounds and compositions of this invention wouldresult in an improvement in an HIV associated ascertainable measurement.Such measurements include, but are not limited to, reduction in viralload in plasma or another defined tissue compartment as measured by,e.g. RT-PCR or branched-chain DNA PCR or culturable virus measurements,β-2 microglobulin or p24 levels, number of CD₄ ⁺ cells or ratio of CD₄ ⁺/CD₈ ⁺ cells, or functional markers such as improvement in quality oflife, ability to carry out normal functions, reduction of dementia, orimmunosuppression-related effects including, but not limited to,opportunistic infections and tumors. The term "prophylacticallyeffective amount" refers to an amount effective in preventing HIVinfection in a patient. As used herein, the term "patient" refers to amammal, including a human.

The term "pharmaceutically acceptable carrier or adjuvant" refers to acarrier or adjuvant that may be administered to a patient, together witha compound of this invention, and which does not destroy thepharmacological activity thereof and is nontoxic when administered indoses sufficient to deliver a therapeutic amount of the antiretroviralagent.

The term "point of attachment" refers to the atom through which a moietyis attached to a specified structure. When a point of attachment may beoptionally methylated, the point of attachment is the carbon atomthrough which a moiety is attached to a specified structure.

The term "substituted", whether express or implied and whether precededby the term "optionally" or not, refers to the replacement of one ormore hydrogen radicals in a given structure with the radical of aspecified substituent. When more than one position in a given structuremay be substituted with a substituent selected from a specified group,the substituents may be either the same or different at every position.Typically, when a structure may be optionally substituted, 0-3substitutions are preferred, and 0-1 substitution is most preferred.Most preferred substituents are those which enhance protease inhibitoryactivity or intracellular antiviral activity in permissive mammaliancells or immortalized mammalian cell lines, or which enhancedeliverability by enhancing solubility characteristics or enhancingpharmacokinetic or pharmacodynamic profiles as compared to theunsubstituted compound. Other most preferred substituents include thoseused in the compounds shown in Table I.

As used herein, the compounds of this invention, including the compoundsof formula I, are defined to include pharmaceutically acceptablederivatives or prodrugs thereof. A "pharmaceutically acceptablederivative or prodrug" means any pharmaceutically acceptable salt,ester, salt of an ester, or other derivative of a compound of thisinvention which, upon administration to a recipient, is capable ofproviding (directly or indirectly) a compound of this invention or aninhibitorily active metabolite or residue thereof. Particularly favoredderivatives and prodrugs are those that increase the bioavailability ofthe compounds of this invention when such compounds are administered toa mammal (e.g., by allowing an orally administered compound to be morereadily absorbed into the blood) or which enhance delivery of the parentcompound to a biological compartment (e.g., the brain or lymphaticsystem) relative to the parent species. Preferred prodrugs includederivatives where a group which enhances aqueous solubility or activetransport through the gut membrane is appended to the explicitly shownhydroxyl in formula (I) or to "E" in formula (I).

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acids includehydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric,maleic, phosphoric, glycollic, lactic, salicylic, succinic,p-toluenesulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic andbenzenesulfonic acids. Preferred acids include hydrochloric, sulfuric,methanesulfonic and ethanesulfonic acids. Methanesulfonic acid is mostpreferred. Other acids, such as oxalic, while not in themselvespharmaceutically acceptable, may be employed in the preparation of saltsuseful as intermediates in obtaining the compounds of the invention andtheir pharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal (e.g.,sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(C₁₋₄alkyl)₄ ⁺ salts.

The term "thiocarbamates" refers to compounds containing the functionalgroup N--SO₂ --O.

The compounds of this invention contain one or more asymmetric carbonatoms and thus occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Allsuch isomeric forms of these compounds are expressly included in thepresent invention. Each stereogenic carbon may be of the R or Sconfiguration. The explicitly shown hydroxyl is also preferred to be synto D, in the extended zig-zag conformation between the nitrogens shownin compounds of formula I.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm "stable", as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a mammal or for use in affinity chromatographyapplications). Typically, such compounds are stable at a temperature of40° C. or less, in the absence of moisture or other chemically reactiveconditions, for at least a week.

The compounds of the present invention may be used in the form of saltsderived from inorganic or organic acids. Included among such acid salts,for example, are the following: acetate, adipate, alginate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.

This invention also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. The basicnitrogen can be quaternized with any agents known to those of ordinaryskill in the art including, for example, lower alkyl halides, such asmethyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkylsulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides; and aralkyl halides including benzyl and phenethylbromides. Water or oil-soluble or dispersible products may be obtainedby such quaternization.

The novel sulfonamides of this invention are those of formula I:##STR2## wherein: each R¹ is independently selected from the groupconsisting of --C(O)--, --S(O)₂ --, --C(O)--C(O)--, --O--C(O)--,--O--S(O)₂, --NR² --S(O)₂ --, --NR² --C(O)-- and --NR² --C(O)--C(O)--;preferably R¹ is --C(O)-- or --O--C(O)--; and most preferably R¹ is--O--C(O)--;

each A is independently selected from the group consisting of 5-7membered non-aromatic monocyclic oxygenated heterocycles containing from1-3 endocyclic oxygens, which may be optionally benzofused, optionallyattached through a C₁ -C₃ alkyl linker, preferably not attached througha linker, and optionally fused with a 5-7 membered monocyclicheterocycle containing from 1-2 endocyclic heteroatoms, preferably notfused, and wherein tetrahydrofuran and tetrahydrofurotetrahydrofuran areexpressly excluded; preferably A is selected from the group consistingof 5-6 membered non-aromatic monocyclic oxygenated heterocyclescontaining from 1-2 endocyclic oxygen atoms, which may be optionallyattached through a C₁ -C₃ alkyl linker and optionally fused with a 5-6membered monocyclic oxygenated heterocycle; more preferably A isdioxanyl, dioxolanyl, dioxolanylmethyl, tetrahydrofurodihydrofuranyl,tetrahydropyranotetrahydrofuranyl or tetrahydropyranodihydrofuranyl;even more preferably A is 1,3-dioxanyl; and most preferably A is1,3-dioxan-5-yl;

each Ht is independently selected from the group consisting of C₃ -C₇carbocycle; C₆ -C₁₀ aryl; phenyl fused with heterocycle; andheterocycle; wherein any member of said Ht may be optionally substitutedwith one or more substituents selected from the group consisting of oxo,--OR², --R², --N(R²)(R²), --NHOH, --R² --OH, --CN, --CO₂ R², --C(O)--N(R²)(R²), --S(O)₂ --N (R²)(R²), --N (R²)--C(O)--R², --C(O)--R²,--S(O)_(n) --R², --OCF₃, --S(O)_(n) --R⁶, --N (R²)--S(O)₂ (R²), halo,--CF₃, --NO₂, --R⁶ and --O--R⁶ ;

each R² is independently selected from the group consisting of H and C₁-C₃ alkyl optionally substituted with R⁶ ;

each R³ is independently selected from the group consisting of H, Ht, C₁-C₆ alkyl and C₂ -C₆ alkenyl wherein any member of said R³, except H,may be optionally substituted with one or more substituents selectedfrom the group consisting of --OR², --C(O)--NH--R², --S(O)_(n)--N(R²)(R²), Ht, --CN, --SR², --CO₂ R², NR² --C(O)--R² ;

each n is independently 1 or 2;

each D and D' is independently selected from the group consisting of R⁶; C₁ -C₅ alkyl, which may be optionally substituted with one or moregroups selected from --OR², --R³, --S--R⁶ '--O--R⁶ and R⁶ ; C₂ -C₄alkenyl, which may be optionally substituted with one or more groupsselected from the group consisting of --OR², --R³, --O--R⁶ and R⁶ ; andC₃ -C₆ carbocycle, which may be optionally substituted with or fusedwith R⁶ ; preferably each D is C₁ -C₅ alkyl, which may be optionallysubstituted with one or more Ht, more preferably D is C₁ -C₅ alkyl,which may be optionally substituted with one group selected from C₆ -C₁₀aryl and C₃ -C₆ carbocycle, even more preferably D is selected from thegroup consisting of benzyl, isobutyl, cyclopentylmethyl andcyclohexylmethyl and most preferably, D is benzyl or isobutyl;preferably each D' is selected from the group consisting of C₁ -C₅ alkyloptionally substituted with R⁶ (wherein each R⁶ is independentlyselected from the group consisting of aryl, carbocycle and heterocycle,wherein said aryl, heterocycle or carbocycle may be optionallysubstituted with one or more groups selected from the group consistingof oxo, --OR⁵, --R⁵, --N(R⁵)(R⁵), --N (R⁵)--C(O)--R⁵, --R⁵ --OH, --CN,--CO₂ R⁵, --C(O)--N(R⁵)(R⁵), halo and --CF₃ and each R⁵ is independentlyselected from the group consisting of H and C₁ -C₃ alkyl), and morepreferably D' is selected from the group consisting of C₁ -C₄ alkyloptionally substituted with one 3-6 membered carbocycle or one 5-6membered heterocycle, and most preferably, D' is selected from the groupconsisting of isobutyl, cyclopentylmethyl and cyclohexylmethyl;

each E is independently selected from the group consisting of Ht;--O--Ht; Ht--Ht; --O--R³ ; --NR² R³ ; C₁ -C₆ alkyl, which may beoptionally substituted with one or more groups selected from the groupconsisting of R⁴ and Ht; C₂ -C₆ alkenyl, which may be optionallysubstituted with one or more groups selected from the group consistingof R⁴ and Ht; and phenyl fused with heterocycle or carbocycle;preferably each E is Ht and more preferably, E is phenyl optionallysubstituted with one or more substituents selected from the groupconsisting of --OR², --R², --N(R²)(R²), --N(R²)--C(O)--R², --R² --OH,--CN, --CO₂ R², --C(O)--N(R²)(R²), halo, and --CF₃ ; or phenyl fusedwith a 5-7 membered heterocycle or carbocycle; and even more preferably,E is phenyl substituted with one substituent selected from the groupconsisting of --OH, --OCH₃, --NH₂, --NHCOCH₃, --SCH₃, and --CH₃ ; orphenyl fused with 5-6 membered heterocycle, and most preferably, E isphenyl substituted with --NH₂ (preferably in the meta- orpara-position);

each R⁴ is independently selected from the group consisting of --OR²,--C(O)--NHR², --S(O)₂ --NHR², halo, --NR² --C(O)--R² and --CN;

each R⁵ is independently selected from the group consisting of H, C₁ -C₄alkyl optionally substituted with aryl; and

each R⁶ is independently selected from the group consisting of aryl,carbocycle and heterocycle, wherein said aryl, carbocycle or heterocyclemay be optionally substituted with one or more groups selected from thegroup consisting of oxo, --OR⁵, --R⁵, --N(R⁵)(R⁵), --N(R⁵)--C(O)--R⁵,--R⁵ --OH, --CN, --CO₂ R⁵, --C(O)--N(R⁵)(R⁵), halo and --CF₃.

In an alternate embodiment of this invention, A is selected from thegroup consisting of 5-7 membered monocyclic heterocycles containing from1-3 heteroatoms, which are methylated at the point of attachment and maybe optionally benzofused, optionally attached through a C₁ -C₃ alkyllinker and optionally fused with a 5-7 membered monocyclic heterocyclecontaining from 1-2 endocyclic heteroatoms; preferably A is selectedfrom the group consisting of 5-6 membered non-aromatic monocyclicoxygenated heterocycles containing from 1-2 endocyclic oxygen atoms,which are methylated at the point of attachment and may be optionallyattached through a C₁ -C₃ alkyl linker and optionally fused with a 5-6membered monocyclic oxygenated heterocycle; more preferably A is3-methyltetrahydrofuranyl, 4-methyltetrahydrofurotetrahydrofuranyl, or5-methyl-1,3-dioxanyl.

Except where expressly noted to the contrary, the term " variable! asdefined for formula I" refers to the definitions shown directly above.

Preferred compounds of formula I include those compounds having at leastone variable defined as the preferred, more preferred, even morepreferred or most preferred definition above. More preferred compoundsof formula I include those compounds having at least two to threevariables defined independently as the preferred, more preferred, evenmore preferred or most preferred definitions above. Most preferredcompounds of formula I include those compounds having at least four tofive variables independently defined as the preferred, more preferred,even more preferred or most preferred definitions above.

Table I illustrates preferred compounds of this invention:

                                      TABLE I                                     __________________________________________________________________________     ##STR3##                                                                     COMPOUND                                                                             A         D         D'       E                                         __________________________________________________________________________     1                                                                                    ##STR4##                                                                                ##STR5##                                                                                ##STR6##                                                                               ##STR7##                                  2                                                                                    ##STR8##                                                                                ##STR9##                                                                                ##STR10##                                                                              ##STR11##                                 3                                                                                    ##STR12##                                                                               ##STR13##                                                                               ##STR14##                                                                              ##STR15##                                 4                                                                                    ##STR16##                                                                               ##STR17##                                                                               ##STR18##                                                                              ##STR19##                                 5                                                                                    ##STR20##                                                                               ##STR21##                                                                               ##STR22##                                                                              ##STR23##                                 6                                                                                    ##STR24##                                                                               ##STR25##                                                                               ##STR26##                                                                              ##STR27##                                7 (Isomer A)                                                                          ##STR28##                                                                               ##STR29##                                                                               ##STR30##                                                                              ##STR31##                                8 (Isomer B)                                                                          ##STR32##                                                                               ##STR33##                                                                               ##STR34##                                                                              ##STR35##                                9 (Isomer A)                                                                          ##STR36##                                                                               ##STR37##                                                                               ##STR38##                                                                              ##STR39##                                10 (Isomer B)                                                                         ##STR40##                                                                               ##STR41##                                                                               ##STR42##                                                                              ##STR43##                                11                                                                                    ##STR44##                                                                               ##STR45##                                                                              CH.sub.3                                                                                ##STR46##                                12                                                                                    ##STR47##                                                                               ##STR48##                                                                               ##STR49##                                                                              ##STR50##                                13                                                                                    ##STR51##                                                                               ##STR52##                                                                               ##STR53##                                                                              ##STR54##                                14                                                                                    ##STR55##                                                                               ##STR56##                                                                               ##STR57##                                                                              ##STR58##                                15                                                                                    ##STR59##                                                                               ##STR60##                                                                               ##STR61##                                                                              ##STR62##                                16                                                                                    ##STR63##                                                                               ##STR64##                                                                               ##STR65##                                                                              ##STR66##                                __________________________________________________________________________

More preferred compounds of this invention are selected from the groupconsisting of compounds 3; 4; 5 and 6 wherein each compound has theformula shown in Table I.

The sulfonamides of this invention may be synthesized using conventionaltechniques. Advantageously, these compounds are conveniently synthesizedfrom readily available starting materials.

The compounds of this invention are among the most readily synthesizedHIV protease inhibitors known. Previously described HIV proteaseinhibitors often contain four or more chiral centers, numerous peptidelinkages and/or require air-sensitive reagents (such as organometalliccomplexes) to effect their synthesis. The relative ease with which thecompounds of this invention can be synthesized represents an enormousadvantage in the large scale production of these compounds.

In general, sulfonamides of formula I are conveniently obtained fromβ-amino acids and their formal derivatives having the general formulaII:

    (W)(Q)N--CH(D)--Y                                          (II)

wherein W is hydrogen or P; P is defined as an amino protecting group; Qis hydrogen, benzyl or A--R¹ --; Y is --C(O)OH, --C(O)H, or --CH₂ OH;and D and A--R¹ -- are as defined above for the compounds of formula I.W and Q may also be taken together with the nitrogen to which they areattached to form a heterocycle, an example of such a construction isphthalimide. Suitable amino protecting groups are described in numerousreferences, including T. W. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 2d Ed., John Wiley and Sons (1991); L. Fieser andM. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, JohnWiley and Sons (1994); and L. Paquette, ed. Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995). Examples of such aminoprotecting groups include, but are not limited to, groups such as Boc,Cbz or Alloc, or alternatively, the amine may be protected as an alkylderivative such as N,N-dibenzyl or trityl. Such α-amino acid derivativesare often commercially available or may be conveniently prepared fromcommercially available α-amino acid derivatives using known techniques.Although this invention envisions the use of racemic mixtures of suchstarting materials, a single enantiomer in the S configuration ispreferred.

Using known techniques, the α-amino acid derivative of general formulaP--N(Q)--CH(D)--COOH may be readily converted to an amino ketonederivative of general formula P--N(Q)--CH(D)--CO--CH₂ --X, wherein P, Qand D are as defined for compounds of formula II and X is a leavinggroup which suitably activates the α-carbon (i.e., increases thesusceptibility of the methylene to nucleophilic attack). Suitableleaving groups are well known in the art and include halides, dialkylsulfonium salts and sulfonates, such as methanesulfonate,trifluoromethanesulfonate or 4-toluenesulfonate. X may also be ahydroxyl which is converted in situ to a leaving group (e.g. bytreatment with a trialkyl- or triarylphosphine in the presence of adialkylazodicarboxylate). Methods for the formation of such amino ketonederivatives also are well known to those of skill in the art (see, forexample, S. J. Fittkau, J. Prakt. Chem., 315, p. 1037 (1973)).Alternatively, certain amino ketone derivatives are commerciallyavailable (e.g., from Bachem Biosciences, Inc., Philadelphia, Pa.).

The amino ketone derivative may then be reduced to the correspondingamino alcohol, represented by the formula P--N(Q)--CH(D)--CH(OH)--CH₂--X, wherein P, Q and D are as defined for compounds of formula II and Xis a leaving group. Alternatively, the amino ketone derivative can bereduced later in the synthetic scheme. Many techniques for reduction ofamino ketone derivatives such as P--N(Q)--CH(D)--CO--CH₂ --X are wellknown to those of ordinary skill in the art (G. J. Quallich and T. M.Woodall, Tetrahedron Lett., 34, p. 785 (1993) and references citedtherein; and Larock, R. C. "Comprehensive Organic Transformations", pp.527-547, VCH Publishers, Inc.© 1989 and references cited therein). Apreferred reducing agent is sodium borohydride. The reduction reactionis conducted at a temperature of from about -40° C. to about 40° C.(preferably, at about 0° C. to about 20° C.), in a suitable solventsystem such as, for example, aqueous or neat tetrahydrofuran or a loweralcohol, such as methanol or ethanol. Although this invention envisionsboth stereospecific and non-stereospecific reduction of the amino ketonederivative P--N(Q)--CH(D)--CO--CH₂ --X, stereoselective reduction ispreferred. Stereoselective reduction may be accomplished by use ofchiral reagents known in the art or by the use of an achiral reducingagent on a chiral substrate. In the present invention, stereoselectivereduction may be conveniently achieved, for instance, undernon-chelating reducing conditions, where chiral induction of the newlyformed hydroxyl group is set by the stereochemistry of the D group(i.e., Felkin-Ahn addition of hydride). We particularly preferstereoselective reductions wherein the resulting hydroxyl is syn to D.We have found that when the hydroxyl group is syn to D, the finalsulfonamide product is an HIV protease inhibitor of higher potency thanthe anti diastereomer.

The hydroxyl group of the amino alcohol may optionally be protected byany known oxygen protecting group (such as trialkylsilyl, benzyl, acetalor alkyloxymethyl) to yield a protected amino alcohol having the formulaP--N(Q)--CH(D)--C(ORT)--CH₂ --X, wherein P, Q and D are as defined forcompounds of formula II, X is a leaving group and R⁷ is H or anysuitable hydroxy protecting group. Several useful protecting groups aredescribed in T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis, 2d Ed., John Wiley and Sons (1991); L. Fieser and M.Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wileyand Sons (1994); and L. Paquette, ed. Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995).

The amino alcohol may then be reacted with a nucleophilic amine compoundto form an intermediate of formula III: ##STR67## wherein W, Q and D areas defined in formula II, R⁷ is H or any suitable oxygen protectinggroup and L is either D' (as described for compounds of formula I) orhydrogen.

Alternatively, an amino acid derivative may be reacted with anucleophilic nitro compound (e.g., a nitromethane anion or a derivativethereof) which can be reduced in one or more steps to yield anintermediate of formula III.

In a particularly advantageous synthetic scheme, simultaneous activationof the methylene and protection of the alcohol may be accomplished byforming an N-protected amino epoxide from the oxygen and its adjacentmethylene to give an intermediate of formula IV: ##STR68## wherein W, Qand D are as defined above for compounds of formula II. Suitable solventsystems for preparing the N-protected amino epoxide include ethanol,methanol, isopropanol, tetrahydrofuran, dioxane, dimethylformamide andthe like (including mixtures thereof). Suitable bases for producing theepoxide include alkali metal hydroxides, potassium t-butoxide, DBU andthe like. A preferred base is potassium hydroxide.

Alternatively, the N-protected amino epoxide may be prepared by reactingan (alkylthio) or (phenylthio)acetic acid dianion with a cyclicN-carboxyanhydride of a protected α-amino acid (such as BOC-Phe-NCA,available from Propeptide). A preferred acetic acid dianion is(methylthio)acetic acid dianion. The resulting amino ketone may then bereduced (e.g., with sodium borohydride). The resulting amino alcohol isreadily converted to the amino epoxide by quaternization (e.g., withmethyl iodide) followed by ring closure (using, for example, sodiumhydride).

Reaction of the N-protected amino epoxide (or other suitably activatedintermediate) with an amine is carried out neat, i.e. in the absence ofsolvent, or in the presence of a polar solvent such as lower alkanols,water, dimethylformamide or dimethylsulfoxide. The reaction can becarried out conveniently between about -30° C. and 120° C., preferablybetween about -5° C. and 100° C. Alternatively, the reaction may becarried out in the presence of an activating agent, such as activatedalumina in an inert solvent, preferably an ether, such as diethyl ether,tetrahydrofuran, dioxane, or tert-butyl methyl ether, conveniently fromabout room temperature to about 110° C., as described by Posner andRogers, J. Am Chem. Soc., 99, p. 8208 (1977). Other activating reagentsinclude lower trialkyl-aluminum species, such as triethylaluminum, ordialkylaluminum halide species, such as diethylaluminum chloride(Overman and Flippin, Tetrahedron Letters, p. 195 (1981)). Reactionsinvolving these species are conveniently carried out in inert solventssuch as dichloromethane, 1,2-dichloroethane, toluene, or acetonitrilebetween about 0° C. and about 110° C. Further methods of displacingleaving groups, or opening epoxides with amines or their equivalentssuch as azides or trimethylsilyl cyanide (Gassman and Guggenheim, J. Am.Chem. Soc. 104, p. 5849 (1982)), are known and will be apparent to thoseof ordinary skill in the art.

Compounds of formulae II, III and IV, and functionality-protectedderivatives thereof, are useful as intermediates for the preparation ofcompounds of formula I. In those cases where L represents D', compoundsof formula III may be converted to compounds of formula I by reactionwith sulfonyl-activated species to form sulfonamides, sulfonyl ureas,thiocarbamates and the like. Methods for preparing suchsulfonyl-activated species are well within the ordinary skill of theart. Typically, sulfonyl halides are used to obtain sulfonamides. Manysulfonyl halides are commercially available; others may be easilyobtained using conventional synthetic techniques (Gilbert, E. E. "RecentDevelopments in Preparative Sulfonation and Sulfation" Synthesis 1969: 3(1969) and references cited therein; Hoffman, R. V."M-Trifluoromethylbenzenesulfonyl Chloride" Org. Synth. Coll. Vol. VII,John Wiley and Sons (1990); Hartman, G. D. et. al. "4-SubstitutedThiophene-and Furan-2-sulfonamides as Topical Carbonic AnhydraseInhibitors" J. Med. Chem., 35, p. 3822 (1992) and references citedtherein. Sulfonyl ureas are usually obtained by the reaction of an aminewith sulfuryl chloride or a suitable equivalent such assulfuryl-bis-imidazole or sulfuryl-bis-N-methyl imidazole.Thiocarbamates are typically obtained by the reaction of an alcohol withsulfuryl chloride or a suitable equivalent such assulfuryl-bis-imidazole or sulfuryl-bis-N-methyl imidazole.

In the case of compounds of formula III wherein L is hydrogen,conversion of the resultant primary amine to a secondary amine may becarried out by known techniques. Such techniques include reaction withan alkyl halide or alkyl sulfonate, or by reductive alkylation with analdehyde or carboxylic acid or activated derivative thereof using, forinstance, catalytic hydrogenation or sodium cyanoborohydride (Borch etal., J. Am. Chem. Soc., 93, p. 2897 (1971)). Alternatively, the primaryamine may be acylated followed by reduction with borane or anothersuitable reducing reagent, for example, as described by Cushman et al.,J. Org Chem., 56, p. 4161 (1991). This technique is especially useful incompounds of formula III where W represents a protecting group such astert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz) and Q is H or whereboth W and Q are benzyl. ##STR69##

If variables W and Q of a particular compound of formula V representremovable protecting groups, removal of either or both groups followedby reaction of the resulting amine with an appropriate activated reagentwill advantageously yield a different compound of formula V. Forinstance, reaction with an activated carboxylate, such as an acyl halide(e.g., acid fluorides, acid chlorides, and acid bromides), an activatedester such as 2- or 4-nitrophenyl esters, haloaryl esters (e.g.,pentafluorophenyl or pentachlorophenyl), or 1-hydroxysuccinimide (HOSu)ester, a carbodiimide activated species, an anhydride, such as asymmetrical anhydride (e.g., isobutyl anhydride), or mixedcarbonic-phosphoric or carbonic-phosphinic anhydrides, will yield thecorresponding amide. Ureas may be obtained by reaction with isocyanatesor amines in the presence of bis-activated carbonic acid derivativessuch as phosgene or carbonyldiimdazole ("CDI"). Carbamates may beobtained by reaction with chlorocarbonates, with carbonates esterifiedwith leaving groups such as 1-hydroxybenzotriazole ("HOBT"), MOSu, or4-nitrophenol or with alcohols in the presence of bis-activated carbonicacid derivatives such as phosgene or its synthetic equivalents includingdiphosgene and triphosgene, or carbonyldiimdazole. Examples of suchcarbonates include, but are not limited to,1,3-dioxan-5-yl-4-nitrophenyl carbonate,3-methyltetrahydrofuran-3-yl-4-nitrophenyl carbonate,4-nitrophenyl-tetrahydropyran-4-yl carbonate,1,3-dioxolan-4-ylmethyl-4-nitrophenyl carbonate,4-nitrophenyl-tetrahydrofurodihydrofuran-4-yl carbonate, and4-nitrophenyl-tetrahydropyranodihydrofuran-4-yl carbonate and the like(see also: A. K. Ghosh, et al. J. Med. Chem. 37, p.2506 (1994)).4-Nitrophenyl carbonates may be obtained by reaction of alcohols and4-nitrophenyl chloroformates by methods known to those skilled in theart. In the reaction of 4-nitrophenyl chloroformate with glycerol formalto give 1,3-dioxan-5-yl-4-nitrophenyl carbonate and1,3-dioxolan-4-ylmethyl-4-nitrophenyl carbonate, more of the dioxanylproduct is produced relative to the dioxolanyl product if more basicconditions are utilized or if bis-4-nitrophenyl carbonate is used inplace of the 4-nitrophenyl formate. While it is preferable to separatethe 1,3-dioxan-5-yl-4-nitrophenyl carbonate and1,3-dioxolan-4-ylmethyl-4-nitrophenyl carbonate products prior tofurther reaction with other amines, the mixture of the two carbonatescan be reacted with a single amine and the two products separated atthat stage. It will be readily recognized that in order to facilitatespecific reactions, the protection of one or more potentially reactivegroups followed by subsequent removal of that group may be required.Such modification to the reaction schemes outlined above are within theordinary skill of the art.

A particularly useful synthetic scheme for producing preferredsulfonamide intermediates of formula VIII is shown below wherein forcompounds of formulas VI, VII and VIII, W and Q are as defined above forcompounds of formula II, D' and E are as defined for compounds offormula I, and P' is H or amino protecting groups: ##STR70##

Compounds of formula VIII may be advantageously synthesized from readilyavailable starting materials such as epoxide VI (see D. P. Getman, J.Med. Chem., 36, p. 288 (1993) and B. E. Evans et al., J. Org. Chem., 50,p. 4615 (1985)). Each step of the above synthetic scheme may be carriedout as generally described above.

As can be appreciated by the skilled artisan, the above syntheticschemes are not intended to comprise a comprehensive list of all meansby which the compounds described and claimed in this application may besynthesized. Further methods will be evident to those of ordinary skillin the art. Additionally, the various synthetic steps described abovemay be performed in an alternate sequence or order to give the desiredcompounds.

The compounds of this invention may be modified by appending appropriatefunctionalites to enhance selective biological properties. Suchmodifications are known in the art and include those which increasebiological penetration into a given biological compartment (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The novel compounds of the present invention are excellent ligands foraspartyl proteases, particularly HIV-1 and HIV-2 proteases. Accordingly,these compounds are capable of targeting and inhibiting late stageevents in HIV replication, i.e., the processing of the viralpolyproteins by HIV encoded proteases. Such compounds inhibit theproteolytic processing of viral polyprotein precursors by inhibitingaspartyl protease. Because aspartyl protease is essential for theproduction of mature virions, inhibition of that processing effectivelyblocks the spread of virus by inhibiting the production of infectiousvirions, particularly from chronically infected cells. Compoundsaccording to this invention advantageously inhibit the ability of theHIV-1 virus to infect immortalized human T cells over a period of days,as determined by an assay of extracellular p24 antigen--a specificmarker of viral replication. Other anti-viral assays have confirmed thepotency of these compounds.

The compounds of this invention may be employed in a conventional mannerfor the treatment of viruses, such as HIV and HTLV, which depend onaspartyl proteases for obligatory events in their life cycle. Suchmethods of treatment, their dosage levels and requirements may beselected by those of ordinary skill in the art from available methodsand techniques. For example, a compound of this invention may becombined with a pharmaceutically acceptable adjuvant for administrationto a virally-infected patient in a pharmaceutically acceptable mannerand in an amount effective to lessen the severity of the viral infectionor to alleviate pathological effects associated with HIV infection orimmunosuppression such as opportunistic infections or various cancers.

Alternatively, the compounds of this invention may be used inprophylactics and methods for protecting individuals against viralinfection during a specific event, such as childbirth, or over anextended period of time. The compounds may be employed in suchprophylactics either alone or together with other antiretroviral agentsto enhance the efficacy of each agent. As such, the novel proteaseinhibitors of this invention can be administered as agents for treatingor preventing HIV infection in a mammal.

The compounds of formula I, especially those having a molecular weightof less than about 700 g/mole, may be readily absorbed into thebloodstream of mammals upon oral administration. Compounds of formula Ihaving a molecular weight of less than about 600 g/mole and aqueoussolubility of greater than or equal to 0.1 mg/mL are most likely todemonstrate high and consistent oral availability. This surprisinglyimpressive oral availability makes such compounds excellent agents fororally-administered treatment and prevention regimens against HIVinfection.

In addition to being orally bioavailable, the compounds of thisinvention also have an impressively high therapeutic index (whichmeasures toxicity versus anti-viral effect). Accordingly, the compoundsof this invention are effective at lower dosage levels than manypreviously described conventional antiretroviral agents and avoid manyof the severe toxic effects associated with those drugs. The potentialof these compounds to be delivered at doses far exceeding theireffective antiviral levels is advantageous in slowing or preventing thepossibility of resistant variants developing.

The compounds of this invention may be administered to a healthy orHIV-infected patient either as a single agent or in combination withother anti-viral agents which interfere with the replication cycle ofHIV. By administering the compounds of this invention with otheranti-viral agents which target different events in the viral life cycle,the therapeutic effect of these compounds is potentiated. For instance,the co-administered anti-viral agent can be one which targets earlyevents in the life cycle of the virus, such as cell entry, reversetranscription and viral DNA integration into cellular DNA. Anti-HIVagents targeting such early life cycle events include, didanosine (ddI),dideoxycytidine (ddC), d4T, zidovudine (AZT), 3TC, 935U83, 1592U89,524W91, polysulfated polysaccharides, sT4 (soluble CD4), ganiclovir,trisodium phosphonoformate, eflornithine, ribavirin, acyclovir, alphainterferon and trimetrexate. Additionally, non-nucleoside inhibitors ofreverse transcriptase, such as TIBO, delavirdine (U90) or nevirapine,may be used to potentiate the effect of the compounds of this invention,as may viral uncoating inhibitors, inhibitors of trans-activatingproteins such as tat or rev, or inhibitors of the viral integrase.

Combination therapies according to this invention exert an additive orsynergistic effect in inhibiting HIV replication because each componentagent of the combination acts on a different site of HIV replication.The use of such combination therapies may also advantageously reduce thedosage of a given conventional anti-retroviral agent which would berequired for a desired therapeutic or prophylactic effect, as comparedto when that agent is administered as a monotherapy. Such combinationsmay reduce or eliminate the side effects of conventional singleanti-retroviral agent therapies, while not interfering with theanti-retroviral activity of those agents. These combinations reducepotential of resistance to single agent therapies, while minimizing anyassociated toxicity. These combinations may also increase the efficacyof the conventional agent without increasing the associated toxicity. Inparticular, we have discovered that in combination with other anti-HIVagents, the compounds of this invention act in an additive orsynergistical manner in preventing the replication of HIV in human Tcells. Preferred combination therapies include the administration of acompound of this invention with AZT, ddI, ddC, d4T, 3TC, 935U83,1592U89, 524W91 or a combination thereof.

Alternatively, the compounds of this invention may also beco-administered with other HIV protease inhibitors such as saquinavir(Ro 31-8959, Roche), MK 639 (Merck), ABT 538 (A-80538, Abbott), AG 1343(Agouron), XM 412 (DuPont Merck), XM 450 (DuPont Merck), BMS 186318(Bristol-Meyers Squibb) and CPG 53,437 (Ciba Geigy) or prodrugs of theseor related compounds to increase the effect of therapy or prophylaxisagainst various viral mutants or members of HIV quasi species.

We prefer administering the compounds of this invention as single agentsor in combination with retroviral reverse transcriptase inhibitors, suchas nucleoside derivatives, or other HIV aspartyl protease inhibitors,including multiple combinations comprising from 3-5 agents. We believethat the co-administration of the compounds of this invention withretroviral reverse transcriptase inhibitors or HIV aspartyl proteaseinhibitors may exert a substantial additive or synergistic effect,thereby preventing, substantially reducing, or completely eliminatingviral replication or infection or both, and symptoms associatedtherewith. Additionally, as the viruses are capable of developingresistance to certain aspartyl protease inhibitors quite rapidly, webelieve that administration of a combination of agents may aid inslowing the development of resistant viruses relative to single agentsalone.

The compounds of this invention can also be administered in combinationwith immunomodulators and immunostimulators (e.g., bropirimine,anti-human alpha interferon antibody, IL-2, GM-CSF, interferon alpha,diethyldithiocarbamate, tumor necrosis factor, naltrexone, tuscarasol,and rEPO); and antibiotics (e.g., pentamidine isethiorate) to prevent orcombat infection and disease associated with HIV infections, such asAIDS, ARC and HIV-associated cancers.

When the compounds of this invention are administered in combinationtherapies with other agents, they may be administered sequentially orconcurrently to the patient. Alternatively, pharmaceutical compositionsaccording to this invention may comprise a combination of an aspartylprotease inhibitor of this invention and one or more therapeutic orprophylactic agents.

Although this invention focuses on the use of the compounds disclosedherein for preventing and treating HIV infection, the compounds of thisinvention can also be used as inhibitory agents for other viruses whichdepend on similar aspartyl proteases for obligatory events in their lifecycle. These viruses include other AIDS-like diseases caused byretroviruses, such as simian immunodeficiency viruses, HTLV-I andHTLV-II. In addition, the compounds of this invention may also be usedto inhibit other aspartyl proteases, and in particular, other humanaspartyl proteases, including renin and aspartyl proteases that processendothelin precursors.

Pharmaceutical compositions of this invention comprise any of thecompounds of the present invention, and pharmaceutically acceptablesalts thereof, with any pharmaceutically acceptable carrier, adjuvant orvehicle. Pharmaceutically acceptable carriers, adjuvants and vehiclesthat may be used in the pharmaceutical compositions of this inventioninclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, self-emulsifying drug delivery systems (SEDDS) suchas dα-tocopherol polyethyleneglycol 1000 succinate, or other similarpolymeric delivery matrices, serum proteins, such as human serumalbumin, buffer substances such as phosphates, glycine, sorbic acid,potassium sorbate, partial glyceride mixtures of saturated vegetablefatty acids, water, salts or electrolytes, such as protamine sulfate,disodium hydrogen phosphate, potassium hydrogen phosphate, sodiumchloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, orchemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solublizedderivatives may also be advantageously used to enhance delivery ofcompounds of formula I.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. We prefer oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal,intralesional and intracranial injection or infusion techniques.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according totechniques known in the art using suitable dispersing or wetting agents(such as, for example, Tween 80) and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are mannitol, water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant such as Ph. Helv or a similar alcohol.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, and aqueous suspensions and solutions. Inthe case of tablets for oral use, carriers which are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried corn starch. Whenaqueous suspensions are administered orally, the active ingredient iscombined with emulsifying and suspending agents. If desired, certainsweetening and/or flavoring and/or coloring agents may be added.

The pharmaceutical compositions of this invention may also beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound of thisinvention with a suitable non-irritating excipient which is solid atroom temperature but liquid at the rectal temperature and therefore willmelt in the rectum to release the active components. Such materialsinclude, but are not limited to, cocoa butter, beeswax and polyethyleneglycols.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For applicationtopically to the skin, the pharmaceutical composition should beformulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation. Topically-transdermal patches arealso included in this invention.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

Dosage levels of between about 0.01 and about 100 mg/kg body weight perday, preferably between about 0.5 and about 75 mg/kg body weight per dayof the active ingredient compound are useful in the prevention andtreatment of viral infection, including infection. Typically, thepharmaceutical compositions of this invention will be administered fromabout 1 to about 5 times per day or alternatively, as a continuousinfusion. Such administration can be used as a chronic or acute therapy.The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. A typicalpreparation will contain from about 5% to about 95% active compound(w/w). Preferably, such preparations contain from about 20% to about 80%active compound.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease.Patients may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

As the skilled artisan will appreciate, lower or higher doses than thoserecited above may be required. Specific dosage and treatment regimensfor any particular patient will depend upon a variety of factors,including the activity of the specific compound employed, the age, bodyweight, general health status, sex, diet, time of administration, rateof excretion, drug combination, the severity and course of theinfection, the patient's disposition to the infection and the judgmentof the treating physician.

The compounds of this invention are also useful as commercial reagentswhich effectively bind to aspartyl proteases, particularly HIV aspartylprotease. As commercial reagents, the compounds of this invention, andtheir derivatives, may be used to block proteolysis of a target peptideor may be derivatized to bind to a stable resin as a tethered substratefor affinity chromatography applications. For example, a compound offormula I may be tethered to an affinity column to purify recombinantlyproduced HIV protease. Derivatization of the compounds of this inventionto produce affinity chromatography resins and the methods used to purifyproteases using such resins are well known and within the skill of theart. These and other uses which characterize commercial aspartylprotease inhibitors will be evident to those of ordinary skill in theart. (See: Rittenhouse, J. et al. Biochem. Biophys. Res. Commun. 171, p.60 (1990) and Heimbach, J. C. et al. Ibid 164, p. 955 (1989)).

In order that this invention be more fully understood, the followingexamples are set forth. These examples are for the purpose ofillustration only and are not to be construed as limiting the scope ofthe invention in any way.

GENERAL MATERIALS AND METHODS

All temperatures are recorded in degrees Celsius. Thin layerchromatography (TLC) was carried out using 0.25 mm thick E. Merck silicagel 60 F₂₅₄ plates and elution with the indicated solvent system.Detection of the compounds was carried out by treating the plate with anappropriate visualizing agent, such as 10% solution of phosphomolybdicacid in ethanol or a 0.1% solution of ninhydrin in ethanol, followed byheating, and/or by exposure to UV light or iodine vapors whenappropriate. Thick layer silica gel chromatography was also carried outusing E. Merck 60 F₂₅₄ plates ("prep plates") of 0.5, 1.0, or 2.0 mmthickness. Following development of the plate, the band of silicacontaining the desired compound was isolated and eluted with anappropriate solvent. Analytical HPLC was carried out using a Water'sDelta Pak, 5 μM silica, C18 reversed-phase column, 3.9 mm ID×15 cm Lwith a flow rate of 1.5 mL/min using the following table:

Mobile phase:

A=0.1% CF₃ CO₂ H in H₂ O

B=0.1% CF₃ CO₂ H in CH₃ CN

Gradient:

T=0 min., A (95%), B (5%)

T=20 min., A (0%), B (100%)

T=22.5 min., A (0%), B (100%)

Preparative HPLC was also carried out using C₁₈ reversed-phase media.HPLC retention times were recorded in minutes. NMR spectral data wasrecorded using a Bruker AMX500, equipped with either a reverse or QNPprobe, at 500 MHz, and was taken in the indicated solvent.

We have measured the inhibition constants of each compound against HIV-1protease using the method described essentially by M. W. Pennington etal., Peptides 1990, Gimet, E. and D. Andrew, Eds., Escom; Leiden,Netherlands (1990).

Compounds of formula I were tested for their antiviral potency inseveral virological assays. In the first assay, the compounds were addedas a solution in dimethylsulfoxide (DMSO) to a test cell culture ofCCRM-CEM cells, a strain of CD4⁺ human T-cell lymphoma cells, previouslyacutely infected with HIV_(IIIb) using standard protocols (see Meek, T.D. et al., "Inhibition of HIV-1 protease in infected T-lymphocytes bysynthetic peptide analogues", Nature, 343, p. 90 (1990). Preferredcompounds are those which are able to inhibit 90% of viral infectivityat a concentration of 1 μM or less. More preferred compounds are thosewhich are able to inhibit 90% of viral infectivity at a concentration of100 nM or less.

The effect of the compounds on inhibiting the replication of the viruswas measured by determining the HIV extracellular p24 antigenconcentration using a commercial enzyme immunoassay (obtained fromCoulter Corporation, Hialeah, Fla.).

Depending on the cell type and the desired readout, syncytia formation,reverse-transcriptase (RT) activity, or cytopathic effect as assayed bya dye uptake method may also be used as readouts of antiviral activity.See H. Mitsuya and S. Broder, "Inhibition of the in vitro infectivityand cytopathic effect of human T-lymphotropic virus typeIII/lymphoadenopathy-associated virus (HTLV-III/LAV) by2',3'-dideoxynucleosides", Proc. Natl. Acad. Sci. USA, vol. 83, pp.1911-1915 (1986). The effect of compounds of formula I on clinicalisolates of other HIV-1 strains was determined by obtaining low-passagedvirus from HIV-infected patients and assaying the effect of theinhibitors in preventing infection of the HIV virus in freshly preparedhuman peripheral blood mononuclear cells (PBMCs).

Insofar as compounds of formula I are able to inhibit the replication ofthe HIV virus in human T-cells and furthermore, may be delivered orallyto mammals, they are of evident clinical utility for the treatment ofHIV infection. These tests are predictive of the compounds ability toinhibit HIV protease in vivo.

EXPERIMENTAL SECTION EXAMPLE 1

N-Cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino))butyl-4-methoxy-benzenesulfonamide(Compound 1).

A. Glycerol formal (1.2 mL, 10.0 mmol) and N-methylmorpholine (1.1 mL,10.0 mmol) were added to a solution of 4-nitrophenylchloroformate (2.01g, 10.0 mmol) in 20 mL of CH₂ Cl₂ at 0° C. The mixture was stirredovernight at room temperature then was washed with 0.5N aq. HCl, water,and brine. The organic phase was dried over MgSO₄ and concentrated.Purification by silica gel column chromatography (hexanes:EtOAc, 4:1)gave 1,3-dioxan-5-yl-4-nitrophenyl carbonate (0.85 g) and1,3-dioxolan-4-ylmethyl-4-nitrophenyl carbonate (0.68 g). ¹ H NMRconsistent with structure.

B. 1,3-Dioxan-5-yl-4-nitrophenyl carbonate (0.079 g, 0.26 mmol) wasadded to a solution of N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-amino)butyl-4-methoxy-benzenesulfonamidehydrochloride salt (0.093 g, 0.198 mmol) and DIEA (0.086 mL, 0.496 mmol)in 1 mL of THF. The mixture was stirred overnight at R.T. whereupon thesolvent was removed in vacuo. Chromatography of this material (10%EtOAc/CH₂ Cl₂) gave the title compound (0.119 g). R_(f) =0.77; CH₂ Cl₂EtOAC, 6:4. HPLC retention time=14.99 min. ¹ H NMR consistent withstructure.

EXAMPLE 2

4-Amino-N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino))butyl-benzenesulfonamide(Compound 3).

A. N-Cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino))butyl-4-nitrobenzenesulfonamide(0.123 g, 0.213 mmol) and a catalytic amount of 10% Pd/C in 5 mL of MeOHwas stirred overnight under an atmosphere of hydrogen. The mixture wasfiltered and concentrated to give the crude product. Purification ofthis material by chromatography (20% EtOAc/CH₂ Cl₂) gave the titlecompound (0.082 g). R_(f) =0.43; CH₂ Cl₂ /EtOAc, 6:4. HPLC retentiontime=14.09 min. ¹ H NMR consistent with structure.

EXAMPLE 3

4-Amino-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-1,3-dioxan-5-yl-oxycarbonylamino)butyl-N-isobutyl-benzenesulfonamide(Compound 4).

A. The procedure described in Example 2A was performed using N-((2 syn,3S)-2-hydroxy-4-phenyl-3-1,3-dioxan-5-yl-oxycarbonylamino)butyl-N-isobutyl-4-nitrobenzenesulfonamide(0.128 g, 0.232 mmol) to give the title compound (0.048 g). R_(f) =0.38;CH₂ Cl₂ /EtOAc, 6:4. HPLC retention time=13.11 min. ¹ H NMR consistentwith structure.

EXAMPLE 4

3-Amino-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-1,3-dioxan-5-yl-oxycarbonylamino)butyl-N-isobutyl-benzenesulfonamide(Compound 5).

A. The procedure described in Example 2A was performed using N-((2 syn,3S)-2-hydroxy-4-phenyl-3-1,3-dioxan-5-yl-oxycarbonylamino)butyl-N-isobutyl-3-nitrobenzenesulfonamide(0.118 g, 0.213 mmol) to give the title compound (0.051). R_(f) =0.23;CH₂ Cl₂ /MeOH, 95:5. HPLC retention time=13.33 min. ¹ H NMR consistentwith structure.

EXAMPLE 5

3-Amino-N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino))butyl-benzenesulfonamide(Compound 6).

A. The procedure described in Example 2A was performed usingN-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino))butyl-3-nitrobenzenesulfonamide(0.128 g, 0.221 mmol) to give the title compound (0.037 g). R_(f) =0.35;CH₂ Cl₂ /MeOH, 95:5. HPLC retention time=14.16 min. ¹ H NMR consistentwith structure.

EXAMPLE 6

N-Cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(1,3-dioxolan-4-yl-methoxycarbonylamino))butyl-4-methoxy-benzenesulfonamide(Compound 2).

A. 1,3-Dioxolan-4-ylmethyl-4-nitrophenyl carbonate (0.086 g, 0.28mmol)(prepared in Example 1A) was added to a solution ofN-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-amino)butyl-4-methoxy-benzenesulfonamidehydrochloride salt (0.102 g, 0.217 mmol) and DIEA (0.087 mL, 0.544 mmol)in 1 mL of THF. The mixture was stirred overnight at R.T. whereupon thesolvent was removed in vacuo. Chromatography of this material (40%EtOAc/CH₂ Cl₂) gave the title compound (0.130 g). R_(f) =0.71; CH₂ Cl₂/EtOAC, 6:4. HPLC retention time=16.02 min. ¹ H NMR consistent withstructure.

EXAMPLE 7

3-Amino-N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(3-methyltetrahydrofuran-3-yl)oxycarbonylamino)butyl-benzenesulfonamide(Compound 15).

A. Methyl magnesium iodide (3.0M in Et₂ O, 20 mL) was added to asolution of tetrahydrofuran-3-one (1.6 g, 18.6 mmol) in 15 mL of Et₂ Oat 0° C. After stirring 4 h at 0° C. the mixture was quenched with sat.aq. NH₄ Cl solution and extracted with Et₂ O. The combined extracts weredried over MgSO₄ and concentrated under reduced pressure to give thecrude material. Purification by chromatography (CH₂ Cl₂ to 1% MeOH/CH₂Cl₂ to 2% MeOH/CH₂ Cl₂) gave 3-hydroxy-3-methyltetrahydrofuran (0.290g). ¹ H NMR consistent with structure.

B. To a solution of 4-nitrophenyl chloroformate (0.86 g, 4.27 mmol) in10 mL of CH₂ Cl₂ was added N-methyl morpholine (0.43 g, 4.25 mmol) and3-hydroxy-3-methyltetrahydrofuran (0.290 g, 2.84 mmol) in 5 mL of CH₂Cl₂. The mixture was stirred overnight at R.T. The solution wasconcentrated under reduced pressure and the resulting material purifiedby chromatography (CH₂ Cl₂ to 10% Et₂ O/CH₂ Cl₂) to give3-methyltetrahydrofuran-3-yl-4-nitrophenyl carbonate (0.560 g). ¹ H NMRconsistent with structure.

C. 3-Methyltetrahydrofuran-3-yl-4-nitrophenyl carbonate (0.100 g, 0.374mmol) was added to a solution of N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-aminobutyl-3-nitrobenzenesulfonamidehydrochloride salt (0.200 g) and triethylamine in 5 mL of CH₂ Cl₂. Themixture was stirred overnight at R.T. whereupon the solvent was removedin vacuo. Chromatography of this material (CH₂ Cl₂ to 10% Et₂ O/CH₂ Cl₂to 1% MeOH/CH₂ Cl₂) gave the nitro sulfonamide (0.200 g). ¹ H NMRconsistent with structure.

D. A solution of the nitro sulfonamide prepared in Example 7C (0.200 g,0.347 mmol) and 10% Pd/C (50 mg) in 5 mL of EtOAc was stirred under anatmosphere of hydrogen for 2 h. The crude product was isolated byfiltration of the mixture and concentration of the filtrate.Purification by chromatography (CH₂ Cl₂ to 1% MeOH/CH₂ Cl₂ to 3%MeOH/CH₂ Cl₂) gave the title compound (0.141 g). R_(f) =0.35; CH₂ Cl₂/MeOH, 8:2. R_(f) =0.63; CH₂ Cl₂ /MeOH/NH₄ OH, 90:10:1. HPLC retentiontime=13.75 min. ¹ H NMR consistent with structure.

EXAMPLE 8

3-Amino-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(3-methyltetrahydrofuran-3-yl)oxycarbonylamino)butyl-N-isobutyl-benzenesulfonamide(Compound 16).

A. The procedure described in Example 7C was performed using N-(2 syn,3S)-2-hydroxy-4-phenyl-3-aminobutyl-N-isobutyl-3-nitro-benzenesulfonamidehydrochloride salt (0.190 g, 0.415 mmol) and3-methyltetrahydrofuran-3-yl-4-nitrophenyl carbonate (0.100 g, 0.374mmol) to give the nitro sulfonamide (0.160 g). ¹ H NMR consistent withstructure.

B. The procedure described in Example 7D was performed using the nitrosulfonamide prepared in Example 8A (0.160 g, 0.291 mmol) and stirringovernight to give the title compound (0.095 g, 63%). R_(f) =0.33; CH₂Cl₂ /EtOAc, 8:2. R_(f) =0.58; CH₂ Cl₂ /MeOH/NH₄ OH, 90:10:1. HPLCretention time=12.93 min. ¹ H NMR consistent with structure.

EXAMPLE 9

3-Amino-N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(S)-tetrahydropyrano-2,3-b!tetrahydrofuran-4-yloxycarbonylamino)butyl-benzenesulfonamide(Compound 7) and 3-Amino-N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(R)-tetrahydropyrano-2,3-b!tetrahydrofuran-4-yloxycarbonylamino)butyl-benzenesulfonamide(Compound 8).

A. The procedure of Example 7C was performed using4-nitrophenyl-tetrahydropyrano- 2,3-b!tetrahydrofuran-4-yl carbonate(0.230 g, 0.74 mmol) and N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-aminobutyl-3-nitro-benzenesulfonamidehydrochloride salt (0.360 g, 0.74 mmol) to give the nitro sulfonamide(0.390 g). ¹ H NMR consistent with structure.

B. The procedure described in Example 7D was performed using the nitrosulfonamide prepared in Example 9A (0.350 g, 0.567 mmol) and stirringovernight to give compound 7 (0.055 g, 16%) and compound 8 (0.029 g, 9%)and a mixed fraction of the two compounds (0.131 g, 39%). ¹ H NMRconsistent with structures. For 8: R_(f) =0.21; CH₂ Cl₂ /EtOAc, 8:2.R_(f) =0.24; CH₂ Cl₂ /MeOH, 97:3. HPLC retention time=14.69 min.

EXAMPLE 10

3-Amino-N-((2 syn, 3S)-2-hydroxy-4-phenyl-3-(S)-tetrahydropyrano-2,3-b!tetrahydrofuran-4-yloxycarbonylamino)butyl-N-isobutyl-benzenesulfonamide(Compound 9) and 3-Amino-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(R)-tetrahydropyrano-2,3-b!tetrahydrofuran-4-yloxycarbonylamino)butyl-N-isobutyl-benzenesulfonamide(Compound 10).

A. The procedure of Example 7C was performed using4-nitrophenyl-tetrahydropyrano- 2,3-b!tetrahydrofuran-4-yl carbonate(0.250 g, 0.81 mmol) and N-(2 syn,3S)-2-hydroxy-4-phenyl-3-aminobutyl-N-isobutyl-3-nitro-benzenesulfonamidehydrochloride salt (0.380 g, 0.80 mmol) to give the nitro sulfonamide(0.310 g). ¹ H NMR consistent with structure.

B. The procedure described in Example 7D was performed using the nitrosulfonamide prepared in Example 10A (0.310 g, 0.524 mmol) and stirringovernight to give compound 9 (0.034 g) and compound 10 (0.047 g). ¹ HNMR consistent with structures. For 9: R_(f) =0.29; CH₂ Cl₂ /EtOAc, 8:2.R_(f) =0.24; CH₂ Cl₂ /MeOH, 97:3. HPLC retention time=13.58 min. For 10:R_(f) =0.25; CH₂ Cl₂ /EtOAc, 8:2. R_(f) =0.23; CH₂ Cl₂ /MeOH, 97:3. HPLCretention time=13.72 min.

EXAMPLE 11

4-Acetamido-N-((2 syn, 3S)-2-hydroxy-4-phenyl-3-tetrahydropyrano-2,3-b!tetrahydrofuran-4-yloxycarbonylamino)butyl-N-methyl-benzenesulfonamide(Compound 11).

A. A solution of 4-acetamido-N-((2 syn,3S)-3-N'-t-butoxycarbonylamino-2-hydroxy-4-phenyl)butyl-N-methyl-benzenesulfonamide(0.100 g, 0.203 mmol) and 10% HCl in EtOAc (20 mL) was stirred for 3 h.The reaction was complete as judged by TLC analysis. The solution wasconcentrated under reduced pressure to give 130 mg of crude amine-HClsalt which was taken up in 5 mL of CH₂ Cl₂ for use in further reactions.

B. The procedure of Example 10A was performed using the amine-HCl saltprepared in Example 11A (2.5 mL of solution) to give the title compound(0.051 g). R_(f) =0.05; CH₂ Cl₂ /MeOH, 97:3. R_(f) =0.47; CH₂ Cl₂/MeOH/NH₄ OH, 90:10:1. HPLC retention time=12.2 and 12.54 min. ¹ H NMRconsistent with structure.

EXAMPLE 12

3-Amino-N-cyclohexylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(S)-tetrahydropyrano-2,3-b!tetrahydrofuran-4-yloxycarbonylamino)butyl-benzenesulfonamide(Compound 12).

A. 3-Nitrophenyl sulfonyl chloride (0.270 g, 1.22 mmol) and solid NaHCO₃(0.140 g, 1.57 mmol) were added to a solution ofN-(3(S)-benzyloxycarbonylamino-2-hydroxy-5-methylhexyl)-N-cyclohexylmethylamine(0.310 g, 0.823 mmol) in 10 mL of CH₂ Cl₂ and 10 mL of sat. aq. NaHCO₃.After stirring overnight at R.T., the solution was diluted with CH₂ Cl₂(100 mL) and the organic layers separated, dried over MgSO₄, andconcentrated under reduced pressure. The resulting crude material waspurified by chromatography (CH₂ Cl₂ to 1% MeOH/CH₂ Cl₂) to give theCbz-amine sulfonamide (0.340 g). ¹ H NMR consistent with structure.

B. TMSCl (1.5 mL, 11.8 mmol) was slowly added to a solution of theCbz-amine sulfonamide prepared in Example 12A (0.340 g, 0.605 mmol) andNaI (0.400 g, 2.67 mmol) in CH₃ CN. After stirring 8 h. at R.T., theorganic phases were concentrated and the residue partitioned betweenEtOAc and water. The organic phases were separated, dried over MgSO₄ andconcentrated. The resulting amine was taken up in 5 mL of CH₂ Cl₂ foruse in further reactions.

C. The procedure described in Example 10A was performed using the amineprepared in Example 12B (2.5 mL of solution) to give the nitrosulfonamide (0.120 g, 66%). ¹ H NMR consistent with structure.

D. The procedure described in Example 7D was performed using the nitrosulfonamide prepared in Example 12A (0.120 g, 0.201 mmol) and stirringovernight to give the title compound (0.029 R_(f) =0.25; CH₂ Cl₂ /MeOH,97:3. R_(f) =0.32; CH₂ Cl₂ /EtOAc, 8:2. HPLC retention time=15.36 and16.79 min. ¹ H NMR consistent with structure.

EXAMPLE 13

3-Amino-N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-tetrahydropyran-4-yloxycarbonylamino)butyl-benzenesulfonamide(Compound 13).

A. A solution of 4-hydroxytetrahydropyran (0.500 g, 49.3 mmol) in 5 mLof CH₂ Cl₂ was added to a solution of 4-nitrophenylchloroformate (1.18g, 5.9 mmol) and N-methyl morpholine (0.59 g, 5.83 mmol) in 10 mL of CH₂Cl₂. After stirring overnight at R.T., the mixture was concentratedunder reduced pressure and the residue purified by chromatography (CH₂Cl₂ to 10% Et₂ O/CH₂ Cl₂) to give 4-nitrophenyl-tetrahydropyran-4-ylcarbonate (1.28). ¹ HNMR consistent with structure.

B. 4-Nitrophenyl-tetrahydropyran-4-yl carbonate (0.100 g, 0.374 mmol)was added to a solution of N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-aminobutyl-3-nitro-benzenesulfonamidehydrochloride salt (0.200 g, 0.413 mmol) and triethylamine (1 mL, 7.17mmol) in 5 mL of CH₂ Cl₂. After stirring overnight at R.T., the mixturewas concentrated under reduced pressure and the residue purified bychromatography (CH₂ Cl₂ to 10% Et₂ O/CH₂ Cl₂ to 1% MeOH/CH₂ Cl₂) to givethe nitro sulfonamide (0.110 g). ¹ H NMR consistent with structure.

C. The procedure described in Example 7D was performed using the nitrosulfonamide prepared in Example 13B (0.110 g, 0.191 mmol) and stirringovernight to give the title compound (0.050 g, 48%). R_(f) =0.24; CH₂Cl₂ /EtOAc, 8:2. R_(f) =0.66; CH₂ Cl₂ /MeOH/NH₄ OH, 90:10:1. HPLCretention time=13.39 min. ¹ H NMR consistent with structure.

EXAMPLE 14

3-Amino-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-tetrahydropyran-4-yloxycarbonylamino)butyl-N-isobutyl-benzenesulfonamide(Compound 14).

A. The procedure described in Example 13B was performed using N-(2 syn,3S)-2-hydroxy-4-phenyl-3-aminobutyl-N-isobutyl-3-nitro-benzenesulfonamidehydrochloride salt (0.190 g, 0.415 mmol) to give the nitro sulfonamide(0.140 g). ¹ H NMR consistent with structure.

B. The procedure described in Example 7D was performed using the nitrosulfonamide prepared in Example 14A (0.140 g, 0.254 mmol) and stirringovernight to give the title compound (0.090 R_(f) =0.24; CH₂ Cl₂ /EtOAc,8:2. R_(f) =0.59; CH₂ Cl₂ /MeOH/NH₄ OH, 90:10:1. HPLC retentiontime=12.55 min. ¹ H NMR consistent with structure.

EXAMPLE 15

We measured the inhibition constants of the compounds listed in Table IIagainst HIV-1 protease using the above-cited method of Pennington et al.

We also measured the anti-viral potency of the compounds in CCRM-CEMcells by the above-cited method of Meek et al. These results are alsoshown in Table II. K_(i) and IC₉₀ values are expressed in nM. Thedesignation "ND" is used where a given compound was not tested.

                  TABLE II                                                        ______________________________________                                        Compound No.     Ki.sup.(nM)                                                                           IC.sub.90.sup.(nM)                                   ______________________________________                                        1                <0.10   5                                                    2                0.30    ND                                                   3                0.10    4                                                    4                0.30    12                                                   5                0.15    7                                                    6                <0.10   5                                                    7                <0.10   ND                                                   8                <0.10   ND                                                   9                0.10    ND                                                   10               <0.10   ND                                                   11               160.    ND                                                   12               1.5     ND                                                   15               0.40    ND                                                   16               1.5     ND                                                   ______________________________________                                    

As demonstrated in Table II, all of the compounds tested displayedsubstantial inhibitory and anti-viral activity. Moreover, several ofthese compounds exhibited activity levels among the highest levels knownto date for HIV protease inhibitors.

While we have described a number of embodiments of this invention, it isapparent that our basic constructions may be altered to provide otherembodiments which utilize the products and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims, rather than by the specificembodiments which have been presented by way of example.

We claim:
 1. A compound of formula I: ##STR71## wherein: each R¹ isindependently selected from the group consisting of --C(O)--, --S(O)₂--, --C(O)--C(O)--, --O--C(O)--, --O--S(O)₂, --NR² --S(O)₂ --, --NR²--C(O)-- and --NR² --C(O)--C(O)--;each A is a 6 membered non-aromaticmonocyclic oxygenated heterocycle containing 2 endocyclic oxygens,optionally attached through a C₁ -C₃ alkyl linker; each Ht isindependently selected from the group consisting of C₃ -C₇ carbocycle;and C₆ -C₁₀ aryl; wherein any member of said Ht is optionallysubstituted with one or more substituents selected from the groupconsisting of oxo, --OR², --R², --N(R²)(R²), --NHOH, --R² --OH, --CN,--CO₂ R², --C(O)--N(R²)(R²), --S(O)₂ --N(R²)(R²), --N(R²)--C(O)--R²,--C(O)--R², --S(O)_(n) --R², --OCF₃, --S(O)_(n) --R⁶, --N(R²)--S(O)₂(R²), halo, --CF₃, --NO₂, --R⁶, --S--CH₃ and --O--R⁶ ; each R² isindependently selected from the group consisting of H and C₁ -C₃ alkyloptionally substituted with R⁶ ; each R³ is independently selected fromthe group consisting of H, Ht, C₁ -C₆ alkyl and C₂ -C₆ alkenyl whereinany member of said R³, except H, is optionally substituted with one ormore substituents selected from the group consisting of --OR²,--C(O)--NH--R², --S(O)_(n) --N(R²)(R²), Ht, --CN, --SR², --CO₂ R², andNR² --C(O)--R² ; each n is independently 1 or 2; each D and D' isindependently selected from the group consisting of R⁶ ; C₁ -C₅ alkyl,which is optionally substituted with one or more groups selected from--OR², --R³, --S--R⁶, --O--R⁶ and R⁶ ; C₂ -C₄ alkenyl, which isoptionally substituted with one or more groups selected from the groupconsisting of --OR², --R³, --O--R⁶ and R⁶ ; and C₃ -C₆ carbocycle, whichis optionally substituted with or fused with R⁶ ; each E isindependently selected from the group consisting of Ht; --O--Ht; Ht--Ht;--O--R³ ; --NR² R³ ; C₁ -C₆ alkyl, which is optionally substituted withone or more groups selected from the group consisting of R⁴ and Ht; C₂-C₆ alkenyl, which is optionally substituted with one or more groupsselected from the group consisting of R⁴ and Ht; and phenyl fused with a5-7 membered carbocycle; each R⁴ is independently selected from thegroup consisting of --OR², --C(O)--NHR², --S(O)₂ --NHR², halo, --NR²--C(O)--R² and --CN; each R⁵ is independently selected from the groupconsisting of H and C₁ -C₄ alkyl optionally substituted with aryl; andeach R⁶ is independently selected from the group consisting of aryl, andcarbocycle, each optionally substituted with one or more groups selectedfrom the group consisting of oxo, --OR⁵, --R⁵, --N(R⁵)(R⁵),--N(R⁵)--C(O)--R⁵, --R⁵ --OH, --CN, --CO₂ R⁵, --C(O)--N(R⁵)(R⁵), haloand --CF₃.
 2. The compound according to claim 1, wherein A is dioxanyl.3. The compound according to claim 2, wherein A is 1,3-dioxanyl.
 4. Thecompound according to claim 3, wherein A is 1,3-dioxan-5-yl.
 5. Acompound of formula I: ##STR72## wherein: each R¹ is independentlyselected from the group consisting of --C(O)--, --S(O)₂ --,--C(O)--C(O)--, --O--C(O)--, --O--S(O)₂, --NR² --S(O)₂ --, --NR²--C(O)-- and --NR² --C(O)--C(O)--;each A is independently selected fromthe group consisting of a 6 membered monocyclic heterocycle, containing2 endocyclic oxygens, which is methylated at the point of attachment andoptionally attached through a C₁ -C₃ alkyl linker; each Ht isindependently selected from the group consisting of C₃ -C₇ carbocycle;and C₆ -C₁₀ aryl; wherein any member of said Ht is optionallysubstituted with one or more substituents selected from the groupconsisting of oxo, --OR², R², --N(R²)(R²), --NHOH, --R² --OH, --CN,--CO₂ R², --C(O)--N(R²)(R²), --S(O)₂ --N(R²)(R²), --N(R²)--C(O)--R²,--C(O)--R², --S(O)_(n) --R², --OCF₃, --S(O)_(n) --R⁶, --N (R²)--S(O)₂(R²), halo, --CF₃, --NO₂, --R⁶, --S--CH₃ and --O--R⁶ ; each R² isindependently selected from the group consisting of H and C₁ -C₃ alkyloptionally substituted with R⁶ ; each R³ is independently selected fromthe group consisting of H, Ht, C₁ -C₆ alkyl and C₂ -C₆ alkenyl whereinany member of said R³, except H, is optionally substituted with one ormore substituents selected from the group consisting of --OR²,--C(O)--NH--R², --S(O)_(n) --N(R²)(R²), Ht, --CN, --SR², --CO₂ R², andNR² --C(O)--R² ; each n is independently 1 or 2; each D and D' isindependently selected from the group consisting of R⁶ ; C₁ -C₅ alkyl,which is optionally substituted with one or more groups selected from--OR², --R³, --S--R⁶, --O--R⁶ and R⁶ ; C₂ -C₄ alkenyl, which isoptionally substituted with one or more groups selected from the groupconsisting of --OR², --R³, --O--R⁶ and R⁶ ; and C₃ -C₆ carbocycle, whichis optionally substituted with or fused with R⁶ ; each E isindependently selected from the group consisting of Ht; --O--Ht; Ht--Ht;--O--R³ ; --NR² R³ ; C₁ -C₆ alkyl, which is optionally substituted withone or more groups selected from the group consisting of R⁴ and Ht; C₂-C₆ alkenyl, which is optionally substituted with one or more groupsselected from the group consisting of R⁴ and Ht; and phenyl fused with a5-7 membered carbocycle; each R⁴ is independently selected from thegroup consisting of --OR², --C(O)--NHR², --S(O)₂ --NHR², halo, --NR²--C(O)--R² and --CN; each R⁵ is independently selected from the groupconsisting of H and C₁ -C₄ alkyl optionally substituted with aryl; andeach R⁶ is independently selected from the group consisting of aryl, andcarbocycle, each optionally substituted with one or more groups selectedfrom the group consisting of oxo, --OR⁵, --R⁵, --N(R⁵)(R⁵),--N(R⁵)--C(O)--R⁵, --R⁵ --OH, --CN, --CO₂ R⁵, --C(O)--N(R⁵)(R⁵), haloand --CF₃.
 6. The compound according to claim 5, wherein A is5-methyl-1,3-dioxanyl.
 7. The compound according to claims 1 or 5,wherein R¹ is --O--C(O)-- or --C(O)--.
 8. The compound according toclaim 7, wherein R¹ is --O--C(O)--.
 9. The compound according to claims1 or 5, wherein D is methyl substituted with a substituent selected fromthe group C₂ -C₅ alkyl, C₃ -C₇ carbocycle and phenyl, which isoptionally substituted with --O--R⁵ or --S-phenyl.
 10. The compoundaccording to claim 9, wherein D is selected from the group consisting ofbenzyl, isobutyl and cyclohexylmethyl.
 11. The compound according toclaims 1 or 5, wherein:each D' is selected from the group consisting ofC₁ -C₆ alkyl optionally substituted with R⁶ ; each R⁶ is independentlyselected from the group consisting of aryl, and 3-6 membered carbocycle,each optionally substituted with one or more groups selected from thegroup consisting of oxo, --OR⁵, --R⁵ --N(R⁵)(R⁵), --N(R⁵)--C(O)--R⁵,--R⁵ --OH, --CN, --CO₂ R⁵, --C(O)--N(R⁵)(R⁵), halo and --CF₃ ; and eachR⁵ is independently selected from the group consisting of H and C₁ -C₃alkyl.
 12. The compound according to claim 11, wherein D' is selectedfrom the group consisting of isobutyl, cyclopentylmethyl andcyclohexylmethyl.
 13. The compound according to claims 1 or 5,wherein:each E is independently phenyl optionally substituted with oneor more substituents selected from the group consisting of --OR², --R²,--N(R²)(R²), --N(R²)--C(O)--R², --R² --OH, --CN, --CO₂ R²,--C(O)--N(R²)(R²), halo, --S--CH₃ and --CF₃ ; or phenyl fused with a 5-7membered carbocycle; each R² is independently selected from the groupconsisting of H and C₁ -C₃ alkyl optionally substituted with R⁶ ; eachR⁶ is independently selected from the group consisting of aryl, and 3-6membered carbocycle each optionally substituted with one or more groupsselected from the group consisting of oxo, --OR⁵, --R⁵, --N(R⁵)(R⁵),--N(R⁵)--C(O)--R⁵, --R⁵ --OH, --CN, --CO₂ R⁵, --C(O)--N(R⁵)(R⁵), haloand --CF₃ ; and each R⁵ is independently selected from the groupconsisting of H and C₁ --C₃ alkyl.
 14. The compound according to claim13, ##STR73## wherein, E is phenyl substituted with one or moresubstituents selected from the group consisting of --OH, --OCH₃, --NH₂,--NHCOCH₃, --S--CH₃, and --CH₃ ; or phenyl fused with a 5-6 memberedcarbocycle.
 15. The compound according to claim 14, wherein E is phenylsubstituted with --NH₂ at the meta- or para-position.
 16. A compoundselected from the group consisting of:N-Cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino))butyl-4-methoxy-benzenesulfonamide;4-Amino-N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino))butyl-benzenesulfonamide;4-Amino-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-1,3-dioxan-5-yl-oxycarbonylamino)butyl-N-isobutyl-benzenesulfonamide;3-Amino-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-1,3-dioxan-5-yl-oxycarbonylamino)butyl-N-isobutyl-benzenesulfonamide;and 3-Amino-N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino))butyl-benzenesulfonamide.17. The compound according to claim 16 selected from the groupconsisting of:4-Amino-N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino))butyl-benzenesulfonamide;4-Amino-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-1,3-dioxan-5-yl-oxycarbonylamino)butyl-N-isobutyl-benzenesulfonamide;3-Amino-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-1,3-dioxan-5-yl-oxycarbonylamino)butyl-N-isobutyl-benzenesulfonamide;and 3-Amino-N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino))butyl-benzenesulfonamide.18. A pharmaceutical composition comprising a pharmaceutically effectiveamount of a compound according to claims 1, 5 or 14 and apharmaceutically acceptable carrier, adjuvant or vehicle.
 19. Thepharmaceutical composition according to claim 18, wherein saidpharmaceutical composition is orally administrable.
 20. Thepharmaceutical composition according to claim 18, further comprising oneor more additional agents selected from the group consisting of otheranti-viral agents and immunostimulators.
 21. The pharmaceuticalcomposition according to claim 20, wherein said other anti-viral agentor agents are protease inhibitors or reverse transcriptase inhibitors.22. The pharmaceutical composition according to claim 21, wherein saidprotease inhibitor or inhibitors are HIV protease inhibitors.
 23. Thepharmaceutical composition according to claim 22, wherein said HIVprotease inhibitor or inhibitors are selected from the group consistingof saquinavir (Ro 31-8959), MK 639, ABT 538 (A80538), AG 1343, XM 412,XM 450 and BMS
 186318. 24. The pharmaceutical composition according toclaim 21, wherein said reverse transcriptase inhibitor or inhibitors arenucleoside analogs.
 25. The pharmaceutical composition according toclaim 24, wherein said nucleoside analog or analogs are selected fromthe group consisting of zidovudine (AZT), dideoxycytidine (ddC),didanosine (ddI), stavudine (d4T), 3TC, 935U83, 1592U89 and 524W91. 26.The pharmaceutical composition according to claim 21, wherein saidreverse transcriptase inhibitor or inhibitors are non-nucleosideanalogs.
 27. The pharmaceutical composition according to claim 26,wherein said non-nucleoside reverse transcriptase inhibitor orinhibitors are delavirdine (U90) or nevirapine.
 28. A method fortreating HIV infection in a mammal comprising the step of administeringto said mammal a pharmaceutically effective amount of a pharmaceuticalcomposition according to either claim
 18. 29. A method for treating HIVinfection in a mammal comprising the step of administering to saidmammal a pharmaceutically effective amount of a pharmaceuticalcomposition according to claim
 20. 30. The method according to claim 28,further comprising the step of concurrently or sequentiallyadministering to the mammal one or more additional agents selected fromthe group consisting of other anti-viral agents and immunostimulators.31. The method according to claim 30, wherein said other anti-viralagent or agents areprotease inhibitors or reverse transcriptaseinhibitors.
 32. The method according to claim 31, wherein said proteaseinhibitor or inhibitors are HIV protease inhibitors.
 33. The methodaccording to claim 32, wherein said HIV protease inhibitor or inhibitorsare selected from the group consisting of saquinavir (Ro 31-8959), MK639, ABT 538 (A80538), AG 1343, XM 412, XM 450, and BMS
 186318. 34. Themethod according to claim 31, wherein said reverse transcriptaseinhibitor or inhibitors are nucleoside analogs.
 35. The method accordingto claim 34, wherein said nucleoside analog or analogs are selected fromthe group consisting of zidovudine (AZT), dideoxycytidine (ddC),didanosine (ddI), stavudine (d4T), 3TC, 935U83, 1592U89 and 524W91. 36.The method according to claim 31, wherein said reverse transcriptaseinhibitor or inhibitors are non-nucleoside analogs.
 37. The methodaccording to claim 36, wherein said non-nucleoside reverse transcriptaseinhibitor or inhibitors are delavirdine (U90) or nevirapine.
 38. Amethod for treating HIV infection in a mammal comprising the step ofadministering to said mammal a pharmaceutically effective amount of apharmaceutical composition according to claim
 19. 39. The methodaccording claim 38, further comprising the step of concurrently orsequentially administering to the mammal one or more additional agentsselected from the group consisting of other anti-vital agents andimmunostimulators.
 40. The method according to claim 39, wherein saidother anti-viral agents are protease inhibitors or reverse transcriptaseinhibitors.
 41. The method according to claim 40, wherein said proteaseinhibitors are HIV protease inhibitors.
 42. The method according toclaim 41, wherein said HIV protease inhibitor is selected from the groupconsisting of saquinavir (Ro 31-8959), MK 639, ABT 538 (A80538), AG1343, XM 412, XM 450, and BMS
 186318. 43. The method according to claim40, wherein said reverse transcriptase inhibitors are nucleosideanalogs.
 44. The method according to claim 43, wherein said nucleosideanalog is selected from the group consisting of zidovudine (AZT),dideoxycytidine (ddC), didanosine (ddI), stavudine (d4T), 3TC, 935U83,1592U89 and 524W91.
 45. The method according to claim 40, wherein saidreverse transcriptase inhibitors are non-nucleoside analogs.
 46. Themethod according to claim 45, wherein said non-nucleoside reversetranscriptase inhibitor is delavirdine (U90) or nevirapine.